BIOCELL Tech Science Press 2021 45(3): 483-487

A short review of the genes involved in the development and progression of colorectal

AMAYNA ZAKARIA; SYED ABDULLAH IBN ASADUZZAMAN; ZOBAYDA NAHAR; HAFSA JARIN SNIGDHA; TASKINA MURSHED; RASHED NOOR*

Department of Life Sciences, School of Environment and Life Sciences, Independent University, Bangladesh (IUB), Dhaka, 1229, Bangladesh

Key words: Colorectal cancer, Genes, Signal transduction pathways

Abstract: The extent and aggression of colorectal cancer is a worldwide public health threat. Extensive research has been conducted on the pre-requisites leading to this fatal cancer. An array of genes along with their and the signal transduction pathways leading to the cellular transformation into the cancerous cells have been investigated. Based on the knowledge gained so far, present review shortly discussed the role of the major genes especially those are involved in instigating abnormalities in the cellular cycles, cellular proliferation and differentiation. A simple but novel molecular scheme of the colorectal cancer development has also been plotted.

Introduction within the right colon may trigger CRC (Medina Pabón and Babiker, 2020). On the contrary, in the case of HPCC-FAP, Defects in genomic organization have been linked to the hundreds or thousands of precancerous adenomatous polyps tumor progression have been suggested (defects in the form that, in turn, instigate the CRC (Medina Pabón and mitotic spindle leading to the formation of malignant Babiker, 2020). tumors) more than one hundred years ago; however, still Akin to the model of an adenoma probably induced by the research on cancer genetics ongoing with the aim of the DNA due to environmental agent(s) or more finding the novel genes as well as the signal transduction specifically by the carcinogenic agents whose continuous pathways that are associated with the abnormal genetic impact resulting in the progression into a carcinoma constitution acquired as a result of mutation (Liu et al., (through a series of molecular signal transduction pathways, 2020; Forootan et al., 2019; Boveri, 1914). Colorectal like the chromosomal instability pathway or CIN, the (CRCs) have long been known to develop through a cascade microsatellite instability pathway, MSI and the serrated of events (i.e., the adenoma-carcinoma sequence) starting adenoma pathway, etc.), the history of knowledge on (1) with the transformation of normal colonic epithelium to an The inherited susceptibilities of the colorectal adenomatous adenomatous intermediate and then ultimately polyps undergoing the malignant transformation (formation adenocarcinoma (Pino and Chung, 2010; Morson, 1974). of cancerous cells) and (2) The progressive research on the Familial adenomatous polyposis (FAP) along with the long-term risk of colorectal cancer is widely known syndromes not related to polyposis; for example, the Lynch effectively starting nearly 45 years ago continuing till date syndrome among the hereditary non-polyposis colorectal (Beggs and Hodgson, 2008; Hill et al., 1978; Muto et al., 1975). cancer (HNPCC), have been reported to be the most Indeed, the multistep genetic model of colorectal frequent cause for the development of the onset of carcinogenesis has been reported thirty years ago, which is hereditary colorectal cancer (HCRC), which is actually a still the accepted model for solid tumors (Fearon and group of syndromes, accounting up to 10% among all cases Vogelstein, 1990). According to the model, (1) The of CRCs including the hereditary polyposis colorectal cancer Adenomatous Polyposis Coli (APC) (HPCC), so far reported (Medina Pabón and Babiker, 2020; is first inactivated, followed by the activation of mutations Valle et al., 2019). Among the HNPCC, the Lynch of the Kirsten rat sarcoma viral oncogene homolog or KRAS fl syndrome (LS) is the most common, whereby the at polyps (belongs to a class of oncogenes which, upon mutation, have the potential to transform normal cells into cancerous ones); *Address correspondence to: Rashed Noor, [email protected] (2) and the succeeding malignant transformation is Received: 22 October 2020; Accepted: 21 December 2020 propelled by the superfluous mutations in the transforming

Doi: 10.32604/biocell.2021.014704 www.techscience.com/journal/biocell

This work is licensed under a Creative Commons Attribution 4.0 International License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 484 AMAYNA ZAKARIA et al.

growth factor-β (TGF-β) signaling pathway (involved in and hyperplastic polyposis syndrome (Beggs and Hodgson, cellular proliferation, differentiation, , extracellular 2008; Sampson et al., 2005). matrix remodeling, angiogenesis, inflammation, etc.); (3) The commonest form of hereditary non-polyposis The phosphatidyl-inositol 3-kinase (PIK3) signaling colorectal cancer is the Lynch syndrome (also known as pathway boosts a major signaling pivot downstream of the Hereditary colorectal cancer syndrome), resulted due to the epidermal growth factor receptor and serves a key role in mutation of the DNA mismatch repair (MMR) enzymes the pathogenesis of several cancers), and (4) finally, the (which recognize and repair the flawed insertion, deletion, TP53 signaling pathways influence the arrest, and mis-incorporation of the DNA bases during replication apoptosis, and angiogenesis (Pino and Chung, 2010; Fearon and recombination); i.e., (1) The mutation of hMSH2 gene and Vogelstein, 1990). The projection of the clinical concept (also known as the caretaker gene which encodes the DNA about colorectal cancer (CRC) is mainly based on the fact MMR protein, MSH2), (2) Human MutL homolog 1 or the that in relation to the size of the colon and rectum, tumors hMLH1 gene (whose mutation may lead to the missense are likely to be of larger size and eventually may pose a codons which in turn trim down the adeptness of MMR), higher cancer rate as measured by repeated colonoscopy, (3) hPMS1 gene (whose mutation may result in the sigmoidoscopy and polypectomy (Atkin et al., 1992). hereditary nonpolyposis colorectal cancer), (4) hPMS2 gene Deciphering the current state of knowledge on the genomics (also encoding the components of the DNA-mismatch of colorectal cancer including (1) The genetic changes in repair complex) and (5) The human mutS homolog 6 or the polyps undergoing the malignant transformation as well as hMSH6 gene which is also known as p160 (encodes the possible epigenomic changes in colorectal polyps; (2) the DNA MMR protein Msh6; and is the homologue of the Mechanism by which the key tumor suppressor gene APC human G/T binding protein, GTBP), is actually the early (adenomatous polyposis coli, whose product, the APC onset of colorectal cancer derived from colorectal protein, plays a grave role in several cellular processes) is endometrial, ovarian, gastric and urinary tract carcinoma mutated (leading to adenomatous polyposis, FAP or the (Lynch et al., 1988). attenuated FAP, i.e., AFAP) provoking colorectal The risk of colorectal carcinogenesis in the untreated carcinogenesis have long been a great interest for cancer FAP patients appears to be is 100%, while among the research (Beggs and Hodgson, 2008). Besides, a study on the attenuated APC variant (i.e., AAPC due to mutations in application of the gene expression profiles of cancer types/ the 3’ and 5’ end of the APC gene accompanied with the subtypes to detect the prognostic genes, as well their clinical mutation in the alternatively spliced exon 9) although implementations, is also going on (Liu et al., 2020). Based the risk remains the same, fewer polyps can be generated on the previous literature, the current review shortly in the late stage of life (Beggs and Hodgson, 2008). described the associated genes (as well as the mutation Interestingly, the FAP-like and AAPC-like phenotypes with points) and the relevant signal transduction pathways the absence of germline mutation in the APC gene have involved in the formation of colorectal cancer. been noticed to carry bi-allelic mutations of the MYH gene by 25% (Venesio et al., 2004). In the 1st–2nd decade of life, Genes Involved in the Development of Colorectal Cancer the Peutz-Jegher Syndrome (PJS) can be expressed which is characterized by the multiple hamartomatous polyps in the CRCs have been reported to develop along with long time gastrointestinal (GI) tract (Juvenile polyposis syndrome) due achieving successive accretion of genetic alterations to the germline mutation of the tumor suppressor gene oppressing (1) The regulators of , (2) The STK11, encoding a serine-threonine kinase which is known cell cycle mechanisms, (3) Apoptosis, and (4) The DNA to regulate the cell polarity, i.e., the cellular proliferation; repair system (Boland and Goel, 2010). The -wide and acts as a tumor suppressor (Beggs and Hodgson, 2008). sequencing projected around 80 mutated genes per Another tumor suppressor, known as the PTEN gene, colorectal tumor; however, nearly 15 among them were encoding the phosphatase and tensin homolog, has been pondered to be the major instigators of tumorigenesis (Pino reported to control the cell growth and proliferation, i.e., the and Chung, 2010; Leary et al., 2008; Wood et al., 2007). The regulation of cell cycle; preventing cells from growing and inherited colorectal cancer syndromes known as the familial dividing too rapidly, and to prevent angiogenesis (a adenomatous polyposis or FAP (as stated earlier), which is precarious step in cancer progression); and hence the caused by germline mutations in the APC gene resulting in somatic mutations of PTEN are likely to be associated with the loss of the second, normal allele of the tumor suppressor the colorectal malignancies as observed through the GI APC gene; and Lynch Syndrome (also known as the polyps (Beggs and Hodgson, 2008; Chow and Baker, 2006). hereditary nonpolyposis colorectal cancer or HNPCC) are In course of colorectal cancer among the children, several indeed easily detectable along with a well understandable important molecular aspects have been discovered: (1) The sequence of genetic mutations which serve as the underlying Juvenile polyposis syndrome (JPS), involving the mutations predisposing factors to instigate colorectal cancer (Beggs in the SMAD2 gene (whose product is known to mediate and Hodgson, 2008). The other inherited variants like the the signal of the TGF-β, thereby regulating the multiple MutY human homolog (MYH) gene (encoding a protein cellular processes including cell proliferation, apoptosis and product of a enzyme which is involved differentiation), (2) Mutation is the SMAD4 gene (encoding in the repair of oxidative DNA damage) whose mutation SMAD4, which is the central mediator of TGF-β signaling has been reported to result in the heritable predisposition to pathway), (3) Mutation in the bone morphogenetic protein colon and stomach cancer as well as to form the polyposis receptor type 1A (BMPR1A) gene, whose product serves as GENETICS OF COLORECTAL CANCER 485

the ligand for the TGF-β superfamily, and has a significant have been noticed to replace the traditional adenoma as the role in cell differentiation; and (4) Finally, the mutation in precursor lesion to the CRC), (7) Mutation of BRAF gene the ENG genes (encoding a component of the TGF-β (encoding the B-Raf protein which is known to be involved receptor complex); and it is also to be noted that these events transmitting signals inside cells that are engaged in directing have been reported throughout the GI tract in a patient with the cell growth), and (8) The CpG island (genome regions the family history of JPS with multiple polyps developed containing a huge number of CpG dinucleotide repeats) before 20 years of age (Sweet et al., 2005). Besides, the methylation, i.e., CpG island methylator phenotype (CIMP) increased frequency of chromosomal 1p allelic loss as well as in colorectal cancers (due to the unusual methylation of the somatic BRAF and k-RAS2 mutations may lead to multiple CpG islands including those in several tumor Hyperplastic polyposis syndrome (Beggs and Hodgson, 2008). suppressor genes) have been well reported so far (Pino and Chung, 2010; Beggs and Hodgson, 2008). CpG (cytosine Pathways Involved in the Development of Colorectal preceding guanine) islands are the regions (rich in CpG dinucleotides) within the genome which are common in the Cancer promoter sites; and several CpG dinucleotides, which Tumor progression involves multiple genetic events remain methylated in normal cells, have been found to be accompanied by genomic instability and mutations unmethylated in case of the colorectal cancer cases (Forootan et al., 2019). As mentioned in the beginning, and (Nazemalhosseini Mojarad et al., 2013). The principal trend has been modeled within Fig. 1, several major signal in the development of tumor depends on the attainment of transduction pathways somatic genetic pathways in leading genomic instability through the distinct pathways in to sporadic colorectal cancer have been identified including colorectal cancer pathogenesis, mainly the CIN pathway, the the (1) Chromosomal instability (CIN) pathway, (2) MSI pathway, and the CpG island methylator phenotype Involvement of the tumor suppressor APC, (3) The K-ras (CIMP) pathways of which the most cases have been (involved in the epidermal growth factor receptor pathway, reported to arise through the CIN pathway, characterized by i.e., the EGFR signaling pathway which regulates growth, the widespread imbalances in the number survival, proliferation, and cellular differentiation) (aneuploidy) and the loss of heterozygosity (LOH) [3]. mutations, (4) Mutation within another tumor suppressor as Multiple pathways have also been reported in the well as the cell cycle regulator , (5) Mutations in the progression of a tumor with a noticeable fraction of MSI TGF-β pathway, the microsatellite instability pathway (MSI) colorectal cancers with the chromosomal abnormalities as leading to the defective DNA mismatch repair, (6) The well as the CIMP phenotype, and CIN-positive tumors have serrated adenoma pathway (whereby the serrated polyps been found to be associated with high levels of MSI;

FIGURE 1. Involvement of the chromosomal instability (CIN), microsatellite instability (MSI), and CpG island methylator phenotype (CIMP) pathways in the development of colorectal cancer. The model consisting of the mutations or the overexpression of the relevant genes along with the associated pathways has been proposed on the basis of the published reports (Nazemalhosseini Mojarad et al., 2013; Boland and Goel, 2010; Pino and Chung, 2010). 486 AMAYNA ZAKARIA et al.

CIMP-positive tumors were linked to the chromosomal Conflicts of Interest: The authors declare that they have no abnormalities (Pino and Chung, 2010; Sinicrope et al., 2006). conflicts of interest to report regarding the present study.

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